This invention relates to the field of opioid receptor probes, and more particularly to a novel method for binding opioid receptors by administration to mammals of a long lasting opioid receptor probe comprising a non-peptide opioid antagonist and another moiety.
While opiates are important in pain perception and induce various behavioral and regulatory effects, the term opioid is used in a broader sense to denote all compounds, including endogenous peptides, that act directly on opioid receptors. Opioid receptors, which are found in both the central nervous system and the peripheral nervous system, were first postulated by Beckett and Casey in 1953, and their existence confirmed in 1973, as described by Terenius, L., in "Stereospecific interaction between narcotic analgesics and a synaptic plasma membrane fraction of rat cerebral cortex," Acta Pharmac. Toxic. 32: 317-320 (1973), Simon, E. J., et al., in "Stereospecific binding of the potent narcotic analgesic (.sup.3 H)Etorphine to rat-brain homogenate," Proc. Natl. Acad. Sci. USA 70: 1947-1949 (1973), and Pert, C. B. and Snyder, S. H., in "Opiate receptor: Demonstration in nervous tissue," Science 179: 1011-1014 (1973).
Previous studies have suggested that endogenous opioids may be involved in the control of feeding and appetite. See, for example, H. N. Bhargava, "Opiate Agonists and Antagonists: Pharmacological, Behavioral, and Neurochemical Effects of Stereoisomers," in "CRC Handbook of Stereoisomers: Drugs in Psychopharmacology", D. F. Smith, Ed., CRC Press, Boca Raton, Fla., 1984, pp. 401-439, and the references cited therein. In particular, it has been demonstrated that the administration of naloxone reduces food intake in animals (for example, mice, rats, guinea pigs, squirrel monkeys) and humans by blockage of opiate receptors, Bhargava, supra; Herman and Holtzman, Life Sci., 34, 1-12 (1984). Yim and Lowy, "Opioids, Feeding, and Anorexias", Federation Proceedings Vol. 43, 14, pp. 2893-2897 (November 1984), reported that administration of the opioid antagonists naloxone and naltrexone were effective in suppressing feeding that had been induced by administration of 2-deoxy-D-glucose.
Hahn, Pasternak et al., J. Neuroscience, 2, 572-576 (1982), discovered that the opiate antagonist naloxone azine has a long lasting effect, i.e., that it is removed only very slowly after having been bound to the sites of opioid receptors. However, Hahn et al. did not disclose any possible use of naloxone azine as a weight control agent.
Other studies of opioid receptor properties have identified several types of receptors, including mu-receptors, kappa-receptors and delta-receptors. Mu-receptors have been associated mainly with sensory systems involving pain, and preferentially bind morphine and most other opiates. Kappa-receptors appear to be involved in analgesia and other central nervous system and peripheral nervous system functions, and bind dynorphins and certain benzomorphans. The classical antagonist naloxone and its congeners are relatively nonselective, but have highest affinities for mu-receptors.
Enkephalins and endorphins are endogenous opioid peptides that are known to interact preferentially with delta-receptors. Delta receptors have been associated with several central nervous system effects, particularly pertaining to the limbic system. It is believed that it is specifically the delta-type opioid receptors that are involved in weight control. Aside from their role in weight regulation, delta-type opioid receptors and endogenous endorphins have been associated with various disorders ranging from epilepsy and schizophrenia to pre-menstrual syndrome. See, for example, Peck, J. Amer. Osteop. Assoc., 82: 192 (1982), and Halbreich and Endicott, Medical Hypotheses, 7: 1045 (1981) with respect to pre-menstrual syndrome. Although certain enkephalin derivatives have been used as delta-selective opioid antagonists, they have several drawbacks as in vivo probes. For example, since enkephalins are peptides, they are metabolically unstable and do not easily cross the blood/brain barrier.
Naloxone has been used to treat pre-menstrual syndrome (see Peck, supra), but has precipitated opioid withdrawal symptoms. It is believed that the withdrawal symptoms result from the relatively large and abrupt dose of naloxone employed for such purposes. Such large concentrated doses are believed necessary for treatment of pre-menstrual syndrome because naloxone is neither delta-selective nor long lasting.
In the development of compositions and methods for weight control and for treatment or prevention of disorders associated with delta-type opioid receptors, there is a need for anorexic or other weight control agents or other opioid receptor probes which are long lasting, generally non-toxic, and substantially free of any other adverse side effects. There is a particular need for compositions which may be administered orally to provide persistent control of weight or treatment or prevention of disorders associated with delta-type opioid receptors, without toxic effects on the recipient.
To locate, identify and determine the concentration of the delta-type of receptors, and to diagnose disorders associated with delta-type opioid receptors, a need exists for improved receptor probes that are long lasting, generally non-toxic, and substantially free of adverse side effects. There is a particular need for compositions which may be administered in vivo to produce persistent and selective blocking of delta-receptors without toxic effects on the recipient.